Hitherto, there are known a number of compounds possessing an anthelmintic activity. Among such compounds, destomycin A, hygromycin B, avermectin and others may be exemplified as such known compounds which are products of microorganisms and which have an anthelmintic activity, but they are of a very small minority among the known anthelmintically active compounds. Takagi et al. made investigations earlier to search for the substances having an anthelmintic activity against roundworms living in domestic fowls, and as a result they discovered PF 1022 substance (which may also be called as PF 1022A substance) as a product of a microorganism, and PF 1022 substance is classified under cyclic depsipeptides having an anthelmintic activity (refer to Japanese Patent Application First Publication Kokai Hei 3-35796, Japanese Patent No.2608479, U.S. Pat. No. 5,116,815 and European Patent Application First Publication No. 0382173A2). This PF 1022 substance is the cyclic depsipeptide represented by the following formula (A): ##STR2## wherein Me stands for methyl group Me has the same meaning in the following descriptions given hereinafter.
PF 1022 substance is a cyclic depsipeptide constituted by L-N-methylleucine [(CH.sub.3).sub.2 CHCH.sub.2 CH(NHCH.sub.3)COOH] (Code: H-L-MeLeu-OH), D-lactic acid [CH.sub.3 CH(OH)-COOH] (Code: H-D-Lac-OH) and D-phenyllactic acid [C.sub.6 H.sub.5 CH.sub.2 CH(OH)COOH] (Code: H-D-PhLac-OH), which are bonded with each other through ester- and amido-bonds. PF 1022 substance may also be represented by the following formula (B).
Formula (B): EQU Cyclo(L-MeLeu-D-Lac-L-MeLeu-D-PhLac-L-MeLeu-D-Lac-L-MeLeu-D-PhLac)(B)
The present inventors further discovered PF 1022B substance, PF 1022C substance and PF 1022D substance as the products of the microorganism, and these substances are PF 1022-related compounds having an anthelmintic activity (refer to Japanese Patent Application First Publication Kokai Hei 5-170749). Further, PF 1022E substance was found as a product of the microorganism (refer to Japanese Patent Application First Publication Kokai Hei 6-184126). The microorganism used here is PF 1022 strain hereinafter described. The structural formulae of PF 1022B to E substances are given in Internationally published specification WO94/19334 (published on 1st September, 1994) of PCT Application PCT/JP94/00252, and in European Patent Application First-published specification No. 0685469A1.
A series of cyclic depsipeptide derivatives which are produced through chemical synthetic processes by the present inventors, as well as some processes for their preparation are described in Japanese Patent Application First Publication Kokai Hei 5-320148 and Japanese Patent Application First Publication Kokai Hei 6-340694 and also in PCT Internationally published specification WO94/19334 mentioned above. Yet further, another series of cyclic depsipeptides prepared by chemical synthesis by Nishiyama et al. and their preparation methods are given in Japanese Patent Application First Publication Kokai Hei 5-229997, Internationally published specification WO93/19053 of PCT Application PCT/JP93/00286, U.S. Pat. No. 5,514,773 and Internationally published specification WO95/07272 of PCT Application PCT/JP94/01446.
In addition, Examples 3 and 8 of the above PCT Internationally published specification WO94/19334 describe PF 1022-002 substance and PF 1022-202 substance, respectively, which were chemically synthesized by the present inventors. PF 1022-002 substance is reported in another name of PF 1022F substance and PF 1022-202 substance is reported in another name of PF 1022H substance in PCT Internationally published specification WO97/11064 (published on Mar. 27, 1997) of PCT Application PCT/JP96/02730(with International filing date: Sep. 20, 1996). The PCT Application PCT/JP96/02730 was filed with claiming a priority from Japanese Patent Application Hei 7-244051 filed on Sep. 22, 1995 and is claiming a series of such novel derivatives of PF 1022 substance which are recently synthesized by the present inventors.
Incidentally, in PCT Internationally published specification WO 97/20945 (published on Jun. 12, 1997) of PCT Application PCT/EP96/05190 (International filing date: Nov. 25, 1996), Jeschke et al. have proposed a process for the preparation of cyclodepsipeptides comprising aryllactic acid as one constituent of the cyclodepsipeptide, which process comprises converting an amino acid such as 4-nitrophenylalanine or a 2-hydroxy carboxylic acid such as 4-nitrophenyllactic acid in the presence of a microbial strain (deposited as DSM 10345) of Mycellia sterilia (which is a generic name of conidium-unformable fungi) or in the presence of an enzyme extracted from said microbial strain.
It is generally known that such diseases called as parasitic diseases can bring about serious damages not only to the health of mankind and animals but also to useful vegetations cultivated in the agriculture. In view of this, there always exist earnest demands for providing some novel and useful substances having an anthelmintic activity, and also for providing some processes capable of producing such novel substances advantageously.
Taking the above-mentioned demands into due consideration, we, the present inventors, had proceeded a series of our investigation earlier, and on the basis of the investigation we already succeeded in providing a new fermentative process for the preparation and a new chemically synthetic process for the preparation of a series of the above-mentioned known or novel cyclic depsipeptides and their derivatives which possess an anthelmintic activity and are therefore useful as therapeutic and preventive medicines for the parasitic diseases.
The above-mentioned PF 1022H substance is a cyclic depsipeptide obtained through a chemical synthesis by the present inventors, and we have further found that this PF 1022H substance is also useful as a starting material for the preparation of a series of depsipeptide derivatives possessing an improved anthelmintic activity, if the functional group or groups of PF 1022H substance is or are chemically modified further.
As measures for preparing the cyclic depsipeptides having such a complex cyclic skeleton as seen in the structural formula (A) above, there are two routes, namely a route by chemical synthesis and another route by cultivation of a microorganism. The fermentative process for preparing the cyclic depsipeptides by cultivation of microorganism shall leave the production of the intended substances of the complex structure to the actions of the microorganism used. In comparison with the chemically synthetic process, the fermentative process is generally advantageous in practice, in respect of the overall period of time required, labors and expenses and other points, and the fermentative process may be operated in a easier and more convenient way.
For the several reasons above-mentioned, the PF 1022F substance and PF 1022H substance are requested to be prepared in a more convenient way by the cultivation of microorganism rather than by the chemical synthetic route. It is also requested that such novel cyclic depsipeptides which have not yet been disclosed in literature are prepared through such convenient, fermentative process by the cultivation of a microorganism, because such novel cyclic depsipeptides will have such possibilities that they possess an anthelmintic activity or some other pharmaceutically useful activities, and that they are utilizable as intermediate materials for chemically synthesizing some other derivatives possessing some useful activities.
One of the objects of this invention is, therefore, to provide a novel process for the preparation of the PF 1022F substance and PF 1022H substance by the cultivation of a microorganism. Another object of this invention is to provide novel, useful cyclic depsipeptides by the cultivation of a microorganism.